We conducted a case-control study of ALS in New England in 1993-96. Specific aims were to characterize potential associations of ALS with (i) lead exposure; (ii) exposure to other neurotoxicants, eg, mercury, solvents and pesticides; (iii) lifestyle factors such as cigarette smoking and diet; and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=110) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. [unreadable] [unreadable] Initial analyses from this study focused on the relationship of ALS to lead exposure. We found that risk of ALS was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each unit increase in log-transformed patella lead, and 2.3-fold for each unit increase in log-transformed tibia lead. These results extend previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers, and suggest a potential role for lead exposure in the etiology of ALS. [unreadable] [unreadable] We also explored the role of genetic susceptibility in ALS. Specifically, we evaluated the relationship of ALS to polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR), which have both been implicated in lead susceptibility. The ALAD 2 allele was associated with decreased lead levels in both patella and tibia, although not in blood, and with 1.9-fold increase in ALS risk. In contrast, the VDR B allele was not associated with lead levels or ALS risk. We also investigated the relationship of ALS to vascular endothelial growth factor (VEGF), an angiogenic growth factor that mediates responses to hypoxia. We confirmed previous reports that risk of ALS is associated with polymorphisms in the VEGF promoter region that determine two specific haplotypes. [unreadable] [unreadable] We used data from this study to explore the relationship of ALS to lifestyle factors. Cigarette smoking was associated with 1.7-fold increase in ALS risk, but alcohol use had no relationship to ALS. Family history of ALS was also associated with increased risk. We examined dietary intake of calcium, magnesium, and antioxidants. Overall, these dietary factors were not related to ALS risk, although modestly protective associations were suggested for magnesium and lycopene.[unreadable] [unreadable] In the past year we used data from this study to look investigate head trauma and survival. For the former, we found that ever having experienced any head injury was nonsignificantly associated with a higher ALS risk. When compared with persons without a head injury, a statistically significant ALS risk elevation was found for participants with more than one head injury (OR: 3.1, 95% CI: 1.2, 8.1) and patients who had had a head injury during the past 10 years (OR: 3.2, 95 percent CI: 1.0, 10.2). For participants who had had multiple head injuries with the latest occurring in the past 10 years, risk was elevated more than 11-fold. We also conducted a meta-analysis of the literature on this topic, which indicated a moderately elevated risk of ALS among persons with previous head injuries (OR: 1.7, 95 percent CI: 1.3, 2.2). In this study population, physical injuries to other body parts, including the trunk, arms, or legs, were not related to ALS risk. These data support the notion that head injury may increase the risk of ALS.[unreadable] [unreadable] We studied survival in ALS using information on date and cause of death retrieved from the National Death Index. We found mortality data for 100 of 110 cases; 93 of 100 death certificates mentioned ALS. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9; 95% confidence interval, 0.81.0) and a stronger inverse association with patella lead (0.5; 0.21.0) and tibia lead (0.3; 0.10.7); similar results were found for survival from symptom onset to death. These unexpected results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression.[unreadable] [unreadable] We have also begun collaborations with researchers at other institutes. In collaboration with researchers from the Karolinska Institute in Sweden, we conducted a nested case-control study based on the Swedish Multi-Generation Register to investigate whether maternal age at delivery and exposure to siblings are associated with an increased risk of ALS. The study comprised 768 ALS cases and five controls per case matched by birth year and gender. Low maternal age (<=20 years) and high maternal age (>41 years) were both associated with higher risk of ALS (OR: 1.5, 95% CI: 1.1, 2.0 and OR: 1.7, 95% CI: 1.1, 2.4, respectively). The relative risk of ALS increased slightly with increasing number of younger siblings (OR: 1.1, 95% CI: 1.0, 1.1; p<0.02). Children who were at least 6 years old when their first younger sibling was born had the greatest relative risk (OR: 1.8, 95% CI: 1.2, 2.7). Exposure to older siblings was not associated with the risk of ALS. Although the strength of the observed associations was modest, these results provided further support for the theory that early life exposures might contribute to disease pathogenesis. We are continuing our collaboration with the researchers from the Karolinska, and a paper on the magnitude of familial risk for ALS has been submitted.[unreadable] [unreadable] We have begun a new data collection effort, the Veterans with ALS and Lead Exposure (VALE) Study, in collaboration with researchers at Duke University and the Durham Veterans Administration Hospital. The VALE study adds a component to an ongoing case-control study of ALS, collecting samples for measurement of heavy metal exposure in order to corroborate our original finding of an association of lead exposure with ALS. Field work for this study is now complete, with recruitment of approximately 175 ALS cases and 225 controls.